Copper-catalyzed multicomponent cascade process for the synthesis of hexahydro-1H-isoindolones

Article abstract of DOI:10.1021/jo0621773

(Chemical Equation Presented) Copper-catalyzed coupling of imines, dienylstannanes, and acryloyl chlorides followed by a Diels-Alder reaction afforded hexahydro-1H-isoindolones. Diversification of the core via Pd-catalyzed cross-coupling defines a new modular approach to isoindolone combinatorial libraries.

Full text of DOI:10.1021/jo0621773

Copper-Catalyzed Multicomponent Cascade
Process for the Synthesis of
Hexahydro-1H-isoindolones
Lei Zhang and Helena C. Malinakova*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe
Hall DriVe, Lawrence, Kansas 66045, and the Center for
Methodology and Library DeVelopment at the UniVersity of
Kansas, 1501 Wakarusa DriVe, Lawrence, Kansas 66047
hmalina@ku.edu
ReceiVed October 19, 2006
FIGURE 1. Synthetic strategy.
traditional isoindolone syntheses,8 diverse substitution patterns
could be created via the choice of the building blocks. This
study provides a proof of concept for a general application of
R-N-substituted amides9 as templates in diversity oriented
synthesis, exploiting just one of many possible methods for an
intramolecular cyclization of two of the four available side
chains.
Initially, the Pd-catalyzed model reactions of benzoyl chloride,
(ethenyl)tributylstannane, and o-bromo- or m- bromo-substituted
imines of arylcarboxaldehydes 1a,b afforded low yields of the
desired R-substituted amides 2a,b (method A, Scheme 1).10 In
contrast, the Cu-catalyzed protocol (method B)5b led to good
(>70%) yields of the corresponding amides 2a,b (Scheme 1).
To establish the substitution pattern required for Diels-Alder
reaction in amides IV, the unprecedented application of a
dienylstannane in the three-component coupling process5 was
investigated (Table 1). Gratifyingly, under the conditions of the
Cu-catalyzed protocol (method B, Scheme 1) the intramolecular
Diels-Alder reaction proved to be quite facile, providing
isoindolones 3 and 5 in a single step, albeit in low yields (30-
40%).11 Reasoning that the Sn-Cu transmetalation12 might
represent a slow step, an excess of the dienylstannane was
employed (2 equiv, method C, Table 1) providing the best yields
(71-75%) of isoindolones 3-5 as inseparable mixtures of major
exo (vide infra) and minor diastereomers accompanied by traces
of a third diastereomer (entries 1-3, Table 1).13
Copper-catalyzed coupling of imines, dienylstannanes, and
acryloyl chlorides followed by a Diels-Alder reaction
afforded hexahydro-1H-isoindolones. Diversification of the
core via Pd-catalyzed cross-coupling defines a new modular
approach to isoindolone combinatorial libraries.
Multicomponent and cascade reactions represent a cornerstone
of combinatorial chemistry.1 Given the role of heterocyles in
drug discovery,2 the present lack of methods for combinatorial
synthesis of biologically relevant3 isoindolone cores is quite
surprising.4 Herein, we report a new tandem copper-catalyzed
three-component coupling/Diels-Alder sequence for a modular
assembly of substituted isoindolones (Figure 1). For the first
time, dienylstannanes III and substituted acryloyl chlorides II
were used in a three-component coupling with imines I
developed by Arndtsen,5 and an appropriate choice of catalyst
permitted the use of imines I bearing an aryl bromide func-
tionality. In most cases, the entire reaction sequence providing
heterocycles V occurred in a one-pot operation. Only the
synthesis of isoindolones V bearing a substituent R6 (R6 ) Me)
required the isolation of amides IV.6 Elaboration of the Csp2-
Br bond in templates V via Pd-catalyzed C-C bond-forming
reactions afforded diversified products VI.7 In contrast to
(8) (a) Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem. Soc.
2005, 127, 2412. (b) Sohar, P.; Csampai, A.; Magyarfalvi, G.; Szabo,
A. E. Stajr, G. Monatsh Chem. 2004, 135, 1519. (c) Clayden, J.; Menet,
C. J.; Mansfield, D. J. Org. Lett. 2000, 2, 4229. (d) Sun, S.; Murray, W. V.
J. Org. Chem. 1999, 64, 5941. (e) Crisp, G. T.; Gebauer, M. G. J. Org.
Chem. 1996, 61, 8425. (f) Brettle, R.; Jafri, I. A. J. Chem. Soc. Perkin
Trans. 1 1983, 387. (g) Brette, R.; Cummings, D. P. J. Chem. Soc. Perkin
Trans. 1 1977, 2385.
(1) Ulaczyk-Lesanko, A.; Hall, D. G. Curr. Opinion Chem. Biol. 2005,
9, 266.
(2) Foye, W. O. Principles of Medicinal Chemistry, 3rd ed.; Lei &
Febinger: Philadelphia, 1989.
(9) For a closely related approach to yohimbine and protoberberine-type
alkaloids, see: Yamaguchi, R.; Hamasaki, T.; Utimoto, K.; Kozima, S.;
Takaya, H. Chem. Lett. 1990, 2161.
(3) Pistelli, L.; Benassi, S.; Migliore, L.; Papa, S.; Andreassi, M. G.
Farmaco 1996, 51, 401.
(10) Arndtsen reported that the Pd-catalyzed coupling proceeded suc-
cessfully with m-iodo-substituted aryl imines, see ref 5c.
(11) An attempted optimization by variations in the Cu(I) salts, additives
(Bu4NBr), temperature, and the catalyst loading led only to a minimal
improvement.
(12) Falck, J. R.; Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995, 117,
5973.
(4) Sun, S.; Murray, W. V. US 99-12364.5 19990310.
(5) (a) Black, D. A.; Arndtsen, B. A. Org. Lett. 2006, 8, 1991. (b) Black,
D. A.; Arndtsen, B. A. J. Org. Chem. 2005, 70, 5133. (c) Davis, J. L.;
Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2004, 43, 590.
(6) Takao, K.; Munakata, R.; Tadano, K. Chem. ReV. 2005, 105, 4779.
(7) Diederich, F., Stang, P. J., Eds. Metal-catalyzed Cross-coupling
Reactions; Wiley-VCH Verlag GmbH: Weinheim, 1998.
(13) The relative configuration of the minor diastereomer and the third
diastereomer could not be assigned.
10.1021/jo0621773 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/23/2007
1484
J. Org. Chem. 2007, 72, 1484-1487

SCHEME 1a
TABLE 1. Reactions with Unsubstituted Acyl Chloride and Diene
Building Blocks
a Method A: Pd2dba3 (2.5%), MeCN/CH2Cl2, rt, 24 h, molar ratios of
reagents: imine/acyl chloride/stannane ) 1:1:1. Method B: CuCl (10%),
MeCN/ CH2Cl2, 45 °C, 16 h, molar ratios of reagents: imine/acyl chloride/
stannane ) 1:1.3:1.
subst
R1
R2
R3
methoda prdt yield (%)
drb
1
2
3
4
5
1a
1b
1c
1d
1e
H
Br Bn
C
C
C
C
D
3
4
5
6
7.1
7.2
74
75
71
68
52f
5f
5.0:1c
2.6:1c
2.3:1c
2.0:1c
(exo)
Br
Me
Me
H
H
H
H
Bn
The N-protecting group provides an additional point of
diversity. N-Allyl imine 1d reacted with acryloyl chloride and
the dienylstannane (Method C) to afford the corresponding
isoindolone 6 (entry 4, Table 1) as an inseparable mixture of
diastereomers with compositions analogous to isoindolones 3-5.
In contrast, using method C, N-PMP imine 1e provided only
the corresponding amide, and heating in toluene was required
to induce the intramolecular Diels-Alder reaction. Ultimately,
a one-pot preparation of isoindolone 7 was realized via a
modified protocol (method D), involving the removal of MeCN/
CH2Cl2 solvent under reduced pressure and heating to reflux in
toluene to afford two diastereomers of isoindolones 7.1 (52%)
and 7.2 (5%) as pure compounds (entry 5, Table 1). The relative
stereochemistry of the major diastereomer of isoindolones 3-7
was assigned as exo on the basis of the comparison of the J
coupling constants for protons on the adjacent carbons C3, C3a,
and C7a, e.g., J3a,7a and J3,3a with the data for structurally closely
related compound 13, the structure of which could be established
by X-ray crystallography.14
Aiming to expand the structural diversity of the diene and
acyl chloride building blocks, the reactivity of substituted
acryloyl chlorides as well as 1-tributylstannyl-1,3-pentadiene,
prepared as a mixture of E/Z isomers (1:2.5),15 was studied
(Table 2). Reactions of imines 1a and 1c with acryloyl chloride
and the terminally substituted dienylstannane employing method
C afforded exclusively the corresponding amides 8a and 8c.
Application of method D (Table 1) gave mixtures of hetero-
cycles 9 and 10 with amides 8. The best results were realized
in a two-pot protocol (method E), incorporating the isolation
and purification of amides 8a,c prior to a reflux in toluene. Imine
1a yielded isoindolones 9.1 (69%) and 9.2 (11%), each as one
diastereomer, and 9.1 accompanied by traces of an additional
Bn
allyld
Br PMPe
a Method C (one pot/one step): CuCl (10%), MeCN/CH2Cl2, 45 °C, 16
h, imine/acyl chloride/stannane ) 1:1.3:2.0. Method D (one pot/two steps):
(i) CuCl (10%), MeCN/ CH2Cl2, 45 °C, 16 h, imine/acyl chloride/stannane
) 1:1.3:2.0; (ii) remove solvents under reduced pressure; (iii) toluene, 110
°C, 16 h. b dr ) major/minor diastereomers as shown. c Trace quantities of
a third diastereomer were detected in the inseparable mixture of two
diastereomers. d Allyl ) CH2CHdCH2. e PMP ) p-MeOC6H4. f Yield of
an isolated single diastereomer.
diastereomer16 (entry 1, Table 2). Imine 1c gave a mixture of
four diastereomers of isoindolone 10 consisting of a major, a
minor, and two trace diastereomers16 (entry 2, Table 2).
Experiments outlined in entries 3-6 (Table 2) demonstrate for
the first time a successful coupling with substituted acryloyl
chlorides, as well as a minimal effect of the additional
substitution on the rates of intramolecular Diels-Alder reac-
tions.6 The coupling of imine 1a with the R-substituted acryloyl
chloride and 1-butadienyl(tributyl)stannane proceeded in one
step (method C) to afford isoindolone 11 (66%, entry 3, Table
2). The one-pot/two-step protocol (method D) afforded good
yields of isoindolones 12-14 from the reactions of imines 1c,
1b, and 1a with â-substituted acryloyl chloride and 1-butadienyl-
(tributyl)stannane (entries 4-6, Table 2). Isoindolone 11 was
isolated as a mixture of two (major and minor) inseparable
diastereomers accompanied by traces of a third unidentified
diastereomer.13 In contrast, a single diastereomer of isoindolones
12-14 was produced. Crystallization of the mixture of diaster-
eomers 11 afforded a single crystal of the major diastereomer
11.1, and a single crystal of isoindolone 13 has also been
obtained. X-ray crystallographic analyses indicated the exo
stereochemistry in both the heterocycles 11.1 and 13, with
opposite configurations at the C3a carbons17 (Table 2). The
relative stereochemistry in the major diastereomers of hetero-
cycles 3-7, 9-10, 12, and 14 was assigned on the basis of
comparable values of the key J coupling constants with the
values for isoindolone 13 (Tables 1 and 2).18 The available
spectral data did not permit an unequivocal assignment of the
relative stereochemistry at the remote C-6 stereocenter in
isoindolones 9-10, and the stereochemistry of the minor and
trace diastereomers.13,18
(14) The values of the coupling constants J3a,7a and J3,3a for the major
products 3-7.1 were analogous to those found for product 13 (see reference
18). In the major (exo) products 3-7.1, the J3a,7a coupling constants equal
approximately 7.0 Hz, and J3,3a coupling constants are in the range of 0-4.5
Hz. However, the structures of the minor products 3-7.2 could not be
assigned. The following values for the coupling constants were found in
the minor products: J3a,7a equal approximately 12.5 Hz, and J3,3a are
approximately 7.5 Hz. Results of additional NOE experiments are presented
in the Supporting Information.
(15) Wender, P.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron
1981, 37, 3967.
(16) The presence of additional diastereomers arises likely from the two
different configurations at the C-6 position (R5), reflecting the presence of
E/Z isomers of the diene.
The configurations of the major products suggest the opera-
tion of transition states VII and VIII (Figure 2). The relative
(17) The spectroscopic data available for the minor product 11.2 did not
permit a conclusive assignment of the relative stereochemistry.
J. Org. Chem, Vol. 72, No. 4, 2007 1485

TABLE 2. Reactions with Substituted Acyl Chloride and Diene
Building Blocks
FIGURE 2. Proposed transition states for Diels-Alder reactions.
TABLE 3
methoda R1 R2 R3
R4
H
R5 prdt yield (%)
drb
1
E
H
Br
H
Me
9.1
9.2
10
11
12
13
14
69c
11d
83
(exo)
2
3
4
5
6
E
Me
H
Me
Br
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
2.0:1e
7.0:1f
(exo)
(exo)
(exo)
C
D
D
D
Br Me
H
H
Br
66
H
H
H
70d
69d
66d
a
Conditions A: p-MeOC6H4B(OH)2, PdCl2(PPh3)2 (10%), K2CO3,
DMF/H2O, 60 °C, 12 h. b Conditions B: methyl acrylate, Pd(OAc)2 (5%),
Na2CO3, Bu4NCl, DMF, 80 °C, 24 h. c Conditions C: phenylacetylene,
PdCl2 (20%), PPh3 (40%), CuI (40%), diethylamine, 48 h.
a Methods C and D (see Table 1). Method E (two pot/two steps): step
1: CuCl (10%), MeCN/CH2Cl2, 45 °C, 16 h, imine/acyl chloride/stannane
) 1:1.3:2.0; step 2: toluene reflux (110 °C). b dr ) molar ratio of major/
minor diastereomers as shown; note the different structure of 11.1. c Yield
of an isolated mixture of the major diastereomer accompanied by traces of
an additional diastereomer. Yield is based on amide 8a. d Isolated yield of
a pure single diastereomer. e Trace quantities of two additional diastereomers
were detected in the inseparable mixture of two (major and minor)
diastereomers. Yield is based on amide 8c. f Trace quantities of a third
diastereomer were detected in the inseparable mixture of two diastereomers.
Structure of compound 11.1 shown indicates the different relative stereo-
chemistry observed in this case.
lones 13 and 14 afforded the anticipated functionalized hetero-
cycles 15-18 in excellent yields (70-95%), demonstrating the
value of the protocol for the construction of diverse combina-
torial libraries.
In conclusion, a new convergent method for a rapid construc-
tion of hexahydro-1H-isoindolones via a tandem Cu-catalyzed
three-component coupling/intramolecular Diels-Alder reaction
has been described. The structures of the isoindolone products
feature up to six substituents that can be diversified by the new
protocol, showcasing the utility of R-N-substituted amides as
templates in diversity oriented synthesis. Studies toward the
application of the protocol to the construction of combinatorial
libraries are ongoing.
stereochemistry at C3 and C3a is reversed in transition state
VIII, apparently due to the presence of the R-methyl group in
the amide side-chain, seeking to relieve the strain that would
be caused by the eclipsed Me and Ar substituents (Figure 2).
Additional diversification of both the m-bromophenyl and
o-bromophenyl substituted isoindolones was achieved via clas-
sical Pd-catalyzed carbon-carbon bond-forming reactions (Table
3).7 Thus, Suzuki, Heck, and Sonogashira coupling to isoindo-
Experimental Section
General Procedure for One-Pot/One-Step Synthesis of Isoin-
dolones (Method C). A solution of the imine (0.5 mmol, 1.0 equiv)
and acid chloride (0.65 mmol, 1.3 equiv) in acetonitrile (3 mL)
was added to a solution of CuCl (5.0 mg, 0.05 mmol, 10 mol %)
in acetonitrile (1 mL). A solution of the dienylstannane (1.0 mmol,
2.0 equiv) in methylene chloride (3 mL) was added, and the reaction
mixture was heated to 45 °C overnight. The reaction mixture was
then concentrated in vacuo and redissolved in ethyl acetate (50 mL).
(18) In the major (exo) products 9.1-10 and 12-14 the J3a,7a coupling
constants equal approximately 7.0 Hz, and J3,3a coupling constants are in
the range of 0-4.5 Hz (compare to data in reference 14). In the minor
products 9.2-10, the J3a,7a equals approximately 12 Hz, and J3,3a coupling
constant are 7 Hz. Notably, the J3,3a coupling constant for isoindolone 11.1
equals 10.6 Hz. Results of additional NOE experiments are presented in
the Supporting Information.
1486 J. Org. Chem., Vol. 72, No. 4, 2007

Saturated aqueous KF solution (15 mL) was added, the mixture
was stirred for 2 h, and the resulting white solid was filtered off
through Celite. The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate (2 × 50 mL). The combined
organic layers were dried (MgSO4), solvents were removed in
vacuo, and the crude product was purified by flash chromatography
over silica eluting with ethyl acetate/hexanes (1:9 followed by 1:4)
to afford the corresponding heterocycles.
(dtd, J ) 10.0 Hz, 7.8 Hz, 1.7 Hz, 1 H, H5), 5.52 (ddt, J ) 10.0
Hz, 3.4 Hz, 1.8 Hz, 1 H, H4), 5.23 (d, J ) 14.9 Hz, 1 H, CH2Ph),
3.98 (d, J ) 4.5 Hz, 1 H, H3), 3.53 (d, J ) 15.0 Hz, 1 H, CH2Ph),
2.70-2.63 (m, 1 H, H3a), 2.57 (t, J ) 7.1 Hz, 1 H, H7a), 2.27
(dm, J ) 17.6 Hz, 1 H, H6R), 2.19 (heptet, J ) 6.0 Hz, 1 H, H7),
1.80 (dm, J ) 17.5 Hz, 1 H, H6â), 1.05 (d, J ) 6.8 Hz, 3H, CH3);
13C NMR (125 MHz, CDCl3) and DEPT δ 175.9 (C), 142.1 (C),
136.1 (C), 131.2 (CH), 130.6 (CH), 129.6 (CH), 128.5 (2 CH),
128.3 (CH), 128.0 (2 CH), 127.5 (CH), 125.2 (CH), 124.9 (CH),
123.2 (C), 65.8 (CH), 45.3 (CH), 44.3 (CH2), 41.5 (CH), 30.2 (CH2),
26.0 (CH), 19.1 (CH3); IR (neat, cm-1) 1695 (s); HRMS (ES+)
calcd for C22H23BrNO (M + H+), 396.0963, found 396.0955.
General Procedure for Suzuki Coupling (Conditions A). To
a solution of isoindolone (0.1 mmol) in DMF/H2O (0.6 mL, 5:1)
were added sodium carbonate (0.2 mmol), boronic acid (0.2 mmol),
and PdCl2(PPh3)2 (0.01 mmol,10 mol %). The flask was flushed
with Ar and sealed, and the reaction mixture was stirred at 60 °C
for 12 h. The reaction mixture was poured into water (3 mL) and
extracted with dichloromethane (3 × 10 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo to afford
the crude product, which was purified by flash chromatography
over silica eluting with ethyl acetate/hexanes (1:4) to afford the
isoindolones 15 or 18. (()-(3R,3aS,7R,7aS)-2,3,3a,6,7,7a-Hexahy-
dro-3-(3-p-methoxyphenylphenyl)-7-methyl-2-(phenylmethyl)-
1H-isoindol-1-one (15). According to conditions A described above,
isoindolone 15 was isolated as a colorless oil (0.035 g, 83%): Rf
) 0.31 (EtOAc/hexane 1:4); 1H NMR (400 MHz, CDCl3) δ 7.57-
7.54 (m, 1 H), 7.53 (d, J ) 8.8 Hz, 2 H), 7.45 (t, J ) 7.6 Hz, 1 H),
7.33-7.26 (m, 4 H), 7.10 (d, J ) 7.6 Hz, 1 H), 7.09-7.05 (m, 2
H), 7.01 (d, J ) 8.8 Hz, 2 H), 5.82 (dtd, J ) 10.0 Hz, 3.8 Hz, 1.7
Hz, 1 H, H5), 5.58 (ddt, J ) 10.0 Hz, 3.4 Hz, 1.8 Hz, 1 H, H4),
5.25 (d, J ) 14.8 Hz, 1 H, CH2Ph), 4.10 (d, J ) 4.7 Hz, 1 H, H3),
3.89 (s, 3 H, OCH3), 3.61 (d, J ) 14.8 Hz, 1 H, CH2Ph), 2.79-
2.72 (m, 1 H, H3a), 2.62 (t, J ) 7.2 Hz, 1 H, H7a), 2.28 (dm, J )
17.5 Hz, 1 H, H6R), 2.21 (hept, J ) 6.1 Hz, 1 H, H7), 1.81 (dm,
J ) 17.3 Hz, 1 H, H6â), 1.17 (d, J ) 6.8 Hz, 3 H, CH3); 13C NMR
(125 MHz, CDCl3) δ 176.1, 159.4, 141.6, 140.0, 136.4, 133.0,
129.4, 128.5 (2 CH), 128.2 (2 CH), 128.0 (2 CH), 128.0, 127.4,
126.4, 125.2, 124.9, 124.8, 114.3 (2 CH), 66.4, 55.4, 45.6, 44.2,
41.7, 30.3, 26.1, 19.2; IR (neat, cm-1) 1690 (s); HRMS (ES+) calcd
for C29H30NO2 (M + H+), 424.2277, found 424.2267.
(()-(3R,3aS,7aS)-2,3,3a,6,7,7a-Hexahydro-3-(2-bromophenyl)-
2-(phenylmethyl)-1H-isoindol-1-one (Exo) and 2,3,3a,6,7,7a-
Hexahydro-3-(2-bromophenyl)-2-(phenylmethyl)-1H-isoindol-1-
one (3). According to the general method C described above,
isoindolone 3 was isolated as a pale yellow oil (0.141 g, 74%) as
a mixture of major (exo) and minor diastereomers in a 5:1 ratio
(containing trace amount of a third diastereomer detected by GC-
MS): Rf ) 0.26 (EtOAc/hexane 1:4); 1H NMR (400 MHz,
CDCl3): δ 7.63 (dd, J ) 7.9 Hz, 1.2 Hz, 1 H), 7.45-6.90 (m, 8
H), 5.93 (dm, J ) 10.0 Hz, 0.83 H), 5.82 (dm, J ) 10.0 Hz, 0.17
H), 5.77 (dm, J ) 10.0 Hz, 0.83 H), 5.48 (ddt, J ) 10.0 Hz, 6.5
Hz, 3.2 Hz, 0.17 H), 5.27 (d, J ) 14.8 Hz, 0.83 H), 5.17 (d, J )
14.8 Hz, 0.17 H), 5.02 (d, J ) 7.7 Hz, 0.17 H, H3), 4.45 (br s,
0.83 H, H3), 3.59 (d, J ) 14.8 Hz, 1 H), 2.98-2.88 (m, 0.17 H,
H3a), 2.84 (dt, J ) 7.2 Hz, 3.7 Hz, 0.83 H, H7a), 2.77-2.70 (m,
0.83 H, H3a), 2.47 (td, J ) 12.5 Hz, 2.4 Hz, 0.17 H, H7a), 2.42-
1.96 (m, 3 H), 1.74-1.61 (m, 1 H); 13C NMR (125 MHz, CDCl3)
and DEPT δ 176.5 (C), 175.9 (C), 175.6 (C), 138.6 (C), 136.4 (C),
135.9 (C), 134.4 (C), 133.7 (CH), 133.2 (CH), 130.2 (CH), 130.0
(CH), 129.6 (CH), 129.6 (CH), 129.5 (CH), 129.2 (CH), 128.8 (CH),
128.7 (CH), 128.7 (CH), 128.5 (3 CH), 128.5 (CH), 127.9 (CH),
127.8 (CH), 127.5 (CH), 126.7 (CH), 126.3 (CH), 124.8 (CH), 124.4
(CH), 124.0 (C), 123.3 (C), 64.8 (CH), 62.3 (CH), 60.9 (CH), 49.6
(CH), 46.2 (CH), 44.8 (CH2), 44.7 (CH2), 44.0 (CH), 51.5 (CH),
40.9 (CH), 38.1 (CH), 25.9 (CH2), 22.3 (CH2), 21.3 (CH2), 20.2
(CH2) (peaks of major isomers are printed in bold, and peaks of
the third isomers (trace amount) are printed in italic if identifiable);
IR (neat, cm-1) 1695 (s); HRMS (ES+) calcd for C21H21BrNO (M
+ H+), 382.0807, found 382.0789.
General Procedure for Two-Step Synthesis of Isoindolones.
Method D (One Pot/Two Step). The three-component coupling
reaction was run as described in method C, heating the reaction
mixture at 45 °C overnight. Solvents were then removed in vacuo,
the crude product was dissolved in toluene (10 mL), and the reaction
mixture was refluxed overnight. The resulting dark precipitate was
filtered off, and solvent was removed in vacuo providing the crude
product, which was purified by flash chromatography over silica
eluting with ethyl acetate/hexanes (1:4) to afford the corresponding
isoindolones.
Acknowledgment. Support for this work from the National
Institutes of Health (KU Center for Methodology and Library
Development, Grant No. P 50 GM069663) is gratefully ac-
knowledged. We thank our colleague Dr. Victor Day (University
of Kansas) for his assistance with X-ray crystallography.
(()-(3R,3aS,7R,7aS)-2,3,3a,6,7,7a-Hexahydro-3-(3-bromophe-
nyl)-7-methyl-2-(phenylmethyl)-1H-isoindol-1-one (13). Accord-
ing to the general method D, described above, isoindolone 13 was
isolated as a white solid (0.136 g, 69%): mp 168-170 °C (CH2-
Cl2/pentane); Rf ) 0.42 (EtOAc/hexane 1:4); 1H NMR (400 MHz,
CDCl3) δ 7.48 (ddd, J ) 8.0 Hz, 1.9 Hz, 1.0 Hz, 1 H), 7.32-7.25
(m, 5 H), 7.08 (d, J ) 7.7 Hz, 1 H), 7.05-7.01 (m, 2 H), 5.81
Supporting Information Available: Description of the syn-
thesis and characterization of all new compounds, including data
from NOE experiments, and X-ray data for compounds 11.1 and
13. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0621773
J. Org. Chem, Vol. 72, No. 4, 2007 1487